[unreadable] There is a pressing need for new drugs to treat HIV infection by virus strains that are resistant to the approved reverse transcriptase and protease inhibitors. Panacos Pharmaceuticals' approach to overcoming drug resistance involves identifying HIV drug candidates with novel mechanisms of action. In collaboration with Professor K.H. Lee of The University of North Carolina at Chapel Hill, Panacos has identified a promising HIV inhibitor, dimethyl succinyl betulinic acid (DSB). DSB potently inhibits HIV replication in vitro and is orally available in rats with a half-life of several hours. During the past few months, new data have been generated on DSB that provide a compelling case for the continued development of this compound. Of particular importance, it has been shown that DSB is the first in a new class of HIV drug candidates that block the last stage in the virus life cycle: budding/maturation. Furthermore, in vitro assays have demonstrated that DSB retains its nanomolar inhibitory activity against drug resistant strains of HIV, including isolates resistant to the three classes of approved drugs. This Phase II SBIR proposal has two major goals: First to identify DSB's molecular target. Mechanism of action studies will focus on targets that have been shown to play a role in HIV budding/maturation and will include determining the effect of DSB on: gag processing (p24-p2 cleavage); interaction between TSG 101 and the gag L domain; RNA dimerization; and cyclophilin incorporation into virions. The second goal is to complete pre-clinical testing of DSB, file an IND and initiate clinical testing of the novel drug candidate, focusing on the study of pharmacokinetics and safety in uninfected volunteers. If the results of pre-clinical testing indicate that DSB does not have suitable properties for clinical development, it will be replaced by a suitable analog generated during the project. The results of initial clinical studies in normal volunteers will be used as the basis to plan and perform efficacy studies in HIV-infected individuals that will be carried out subsequent to the Phase II grant period. [unreadable] [unreadable] [unreadable]